Genistein inhibits voltage-gated sodium currents in SCG neurons through protein tyrosine kinase-dependent and kinase-independent mechanisms
Genistein inhibits voltage-gated sodium currents in SCG neurons through protein tyrosine kinase-dependent and kinase-independent mechanisms
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金雀异黄素通过蛋白酪氨酸激酶依赖性和激酶非依赖性机制抑制 SCG 神经元中的电压门控钠电流
DOI：
10.1007/s00424-008-0444-2
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发表时间：
2008-08-01
影响因子：
4.5
通讯作者：
Zhang, Hailin
中科院分区：
文献类型：
--
作者：
Jia, Zhanfeng;Jia, Yueqin;Zhang, Hailin
电压门控钠通道在神经元动作电位的起始和传播中起着重要作用。染料木黄酮是一种植物雌激素，长期以来被用作蛋白酪氨酸激酶（PTK）的广谱抑制剂。此外，染料木黄酮诱导的离子通道的调节已经在先前的文献中描述。本研究观察了染料木黄酮对大鼠颈上级神经节（SCG）电压门控钠通道的影响。结果表明，染料木黄酮呈浓度依赖性地抑制Na+电流，半数效应浓度（IC_（50））为9.1 ± 0.9 μM。染料木黄酮积极转移的电压依赖性的激活，但不影响失活的Na+电流。非活性染料木黄酮类似物大豆苷元也抑制Na+电流，但不如染料木黄酮有效。大豆苷元诱导的抑制IC_（50）为20.7 ± 0.1 μM。钒酸盐，蛋白酪氨酸磷酸酶的抑制剂，部分但显着逆转染料木素诱导的抑制Na+电流。其他蛋白酪氨酸激酶拮抗剂，如tyrphostin 23，erbstatin类似物，和PP2都有小，但显着的抑制作用Na+电流。在所有活性和非活性酪氨酸激酶抑制剂测试，染料木素是最有效的抑制剂的Na+电流。这些结果表明，金雀异黄素抑制Na+电流在大鼠SCG神经元通过两种不同的机制：蛋白酪氨酸激酶独立的，和蛋白酪氨酸激酶依赖的机制。此外，Src激酶家族可能参与Na+通道的基础磷酸化。
AbstractVoltage-gated sodium channels play a crucial role in the initiation and propagation of neuronal action potentials. Genistein, an isoflavone phytoestrogen, has long been used as a broad-spectrum inhibitor of protein tyrosine kinases (PTK). In addition, genistein-induced modulation of ion channels has been described previously in the literature. In this study, we investigated the effect of genistein on voltage-gated sodium channels in rat superior cervical ganglia (SCG) neurons. The results show that genistein inhibits Na+currents in a concentration-dependent manner, with a concentration of half-maximal effect (IC50) at 9.1 ± 0.9 μM. Genistein positively shifted the voltage dependence of activation but did not affect inactivation of the Na+current. The inactive genistein analog daidzein also inhibited Na+currents, but was less effective than genistein. The IC50for daidzein-induced inhibition was 20.7 ± 0.1 μM. Vanadate, an inhibitor of protein tyrosine phosphatases, partially but significantly reversed genistein-induced inhibition of Na+currents. Other protein tyrosine kinase antagonists such as tyrphostin 23, an erbstatin analog, and PP2 all had small but significant inhibitory effects on Na+currents. Among all active and inactive tyrosine kinase inhibitors tested, genistein was the most potent inhibitor of Na+currents. These results suggest that genistein inhibits Na+currents in rat SCG neurons through two distinct mechanisms: protein tyrosine kinase-independent, and protein tyrosine kinase-dependent mechanisms. Furthermore, the Src kinase family may be involved in the basal phosphorylation of the Na+channel.